HU191096B - Process for producing new diazabicyclo /3.3.1/ nonane derivatives - Google Patents

Abstract

3,7-diaza bicyclo-(3,3,1)-nonane compounds of the formula <IMAGE> I in which substituents R1, R2, R3, R4, Z1, and Z2 indicate the substituents as they are given in the description of the invention, can be employed to produce certain pharmaceutically useful compounds.

Description

PROCESS FOR THE MANUFACTURE OF NEW DIAZABICYCLO [3.3.1] NONANE DERIVATIVES (57)

The present invention relates to novel 3,7-diazabicyclo [3.3.1] nonane derivatives of the formula I and their pharmaceutically acceptable acid addition salts. In the formula>

Z) and Z ₂ together form an oxo group or independently represent a hydrogen atom;

R 1 and R ₂ are each independently hydrogen, C 1 -C 12 alkyl, C 2 -C 6 alkenyl, or C 3 -C 6 alkylcycloalkyl bonded via a C 1 -C 3 alkylene group;

. R ₃ and R ₄ are each independently C 1 -C 6 alkyl or together form a C 3 -C 6 alkylene group;

with the condition that

A) where R, and R ₂ is hydrogen, and

i) Z ₁ and Z _{2 are taken} together to form an oxo group other than R ₃ and / or R 2 or together with a ladder or pentamethylene group; or ii) Z ₁ and Z ₂ are each hydrogen, at least one of R ₃ and R ₄ being different from one of the edges; obsession

B) if only one of R ₁ and R ₂ is hydrogen then at least one of R ₃ and R ₄

(l) (III) (IV)

191 096, other than one of methyl, or together of tetra or pentamethylene, when the other of R ₁ and R ₂ is methyl or ethyl; obsession

C) when both R ₁ and R ₂ are other than hydrogen, then R 1 to R ₄ together have at least 5 carbon atoms.

The compounds of formula (I) are prepared starting from the dinitriles of formula (111) or the inononitriles of formula (IV).

Derivatives of the compounds of formula I wherein Z ₁ and Z ₂ are each hydrogen and R 1 and R _{2 are} other than hydrogen have valuable antiarrhythmic activity. The other compounds of formula (1), also new, are valuable pharmaceutical intermediates.

The present invention relates to novel diazabicyclo [3.3.3.1] nonane derivatives, their pharmaceutically acceptable acid addition salts and pharmaceutical compositions containing them.

There are many publications in the literature dealing with

3,7-diazabicyclo [3.3.l] nonáii-szárniazékokkal. Some publications in the chemical family of this compound family (e.g., Russian. Chem. Rev. 34, 439 (1965), Anni, Ist. Super Sanita 4, 157 (1968), J. Org. Chem. 33, 355 (1968), Russian) Chem. Rev. 42, 190 (1973), Chem. Bér. 110, 3894 ff., Austral J. Chem. 13 (1960), 129 ff., J. Chem. Soc. 115 (1919), 686 ff. (e.g., Eur. J. Med. Chem. 1977, pp. 301-305), The described pharmacological effects from the weak local anesthetic effect (1. Chem. Soc. 1951, 1706), through the central nervous system (2,658). German Patent Publication Nos. 558 and 2,749,584) extend to the antiarrhythmic effect (see German Patent Publication Nos. 2,428,792, 2,726,571 and 2,744,248).

It is an object of the present invention to provide novel diazabicyclo [3.3.1] nonane derivatives having a modified activity profile. It is another object of the present invention to provide novel diazabicyclo [3.3.1] nonane derivatives which are useful as intermediates in the preparation of novel diazabicyclo [3.3.1] nonane derivatives.

The present invention relates to a process for the preparation of novel compounds of the formula I and their pharmaceutically acceptable acid addition salts

Z ₁ and Z ₂ together form an oxo group or independently represent a hydrogen atom;

R 1 and R ₂ are each independently hydrogen, C 1 -C 12 alkyl, C 2 -C 6 alkenyl, or C 3 -C 6 alkylcycloalkyl attached via C 1 -C 3 alkylene;

R 1 and R ₄ each independently represent C 1-6 alkyl or together form C 3-6 alkylene;

with the condition that

A) when R 1 and R ₂ are hydrogen atoms

i) Z and Z _{2 are taken} together to form an oxo group, other than R ₃ and / or R ₄ , or together other than tetra or pentamethylene; or ii) Z ₁ and Z ₂ are each hydrogen, at least one of R ₃ and R ₄ is other than methyl; obsession

B) if only one of R ₁ and R ₂ represents 2 hydrogen atoms, then at least one of R ₃ and R _{4 has} different meaning from methyl or taken together with other than 5 tetra or pentamethylene groups, if the other of R ₁ and R ₂ is methyl or represents an ethyl group; obsession

C) when both R and R ₂ are hydrogen

2Q has different meanings, so that the groups R 1 -R ₄ together contain at least 5 carbon atoms).

A preferred embodiment of the process of the present invention relates to the preparation of compounds of formula I wherein R 1 and / or R ₂ 'each contain up to 7 carbon atoms.

^2-3 The alkyl group at the R and R ₂ positions may be straight or branched. The free alkyl group is preferably methyl, ethyl, n-propyl, η-butyl, n-pentyl, n-hexyl or n-heptyl, while the branched chain

The 3q alkyl group is preferably selected from the group consisting of isopropyl, secondary butyl (2-methylpropyl), 3-melylbutyl, 2,2-dimethylpropyl, 2-methylpentyl and 3,3-dimethylbutyl. .

The alkenyl at R ₁ and R ₂ may also be straight or branched. Among the straight-chain alkenyl groups are allyl (2-propenyl), 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl or 4-pentenyl, while the branched alkylene group is 2-ethyl 2-propenyl is mentioned.

Further, R ₁ and R ₂ may also be a C 3 -C 9 cycloalkyl group attached to the nitrogen atom via an alkylene group. The cycloalkyl group may be attached to the nitrogen atom via a C 1-3 alkylene group, preferably a methylene group. Among these groups, e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; they may be attached to the nitrogen atom via a C 1-3 alkylene group, preferably a methylene group.

R and R ₂ as mentioned above may be the same or different.

Preferably R 1 and R _{2 have the} same meaning, especially when R ₃ and R ₄ represent different groups.

Preferably R ₃ and R ₄ are alkyl, especially linear alkyl. These groups correspond ineg defined for R, and R ₂ interpreting. R ₃ and R _{4 represent} 1-6, especially 1-4 carbon atoms.

R ₃ and R _{4 may have the} same or different meanings, θθ R ₃ and R ₄ preferably represent the same groups, especially when R 1 and R _{2 have} different meanings.

In one embodiment of the process of the present invention, gc is a compound of formula (I)

191 096 wherein R ₃ and R ₄ together form an alkylene group of the formula - (CH ₂ ) _n -; n is preferably 3-6, especially 3-5.

A subset of the compounds of formula (I) are those, wherein Zi and Z ₂ together represent oxo. These compounds are valuable intermediates useful in the preparation of diazabicyclo [3.3.1] nonane compounds which are particularly effective in medicine.

This group includes compounds of formula (I) wherein R ₁ and R _{2 are} hydrogen. Preferred examples of this compound (group) are the 2,4,6,8-tetraoxo-3,7-diazabicyclo [3.3.1] nonane derivatives of formula II wherein R 1 is hydrogen.

Also included in this group are compounds of formula I wherein R 1 is only one of cs R ₂ represents a hydrogen atom. Preferred compounds of this group are compounds of formula Va.

This group further includes compounds of formula I wherein R 1 and R ₂ are each other than hydrogen. These compounds correspond to the formula (Vb) or (Ve).

In the formula (Ve), R ₆ is the same as R ₁ or R ₂ . In the compounds of the formula (Ve), the two R _{6 's are the} same groups and thus are symmetrically substituted compounds.

Another subgroup of compounds of formula I are those wherein Z ₁ and Z _{2 are} each hydrogen.

This group includes compounds having R ₁ and R _{2 being} hydrogen (i.e., compounds of formula (VIa)) and derivatives wherein only one of R 1 and R 1 is hydrogen (i.e., (VIb) and (VIc)). compounds of formula I].

These compounds are also valuable intermediate intermediates for the preparation of diazabicyclo [3.3.1] nonane dehydrogenases, which are particularly pharmaceutically valuable.

The present invention further relates to the preparation of compounds of general formula (I) wherein Z ₁ and Z _{2 are} each hydrogen and R ₁ and R _{2 are} not hydrogen. In case of symmetrical substitution or formula (VIIa) These compounds have the formula (VHb) (where Re is R or R ₂ the same report).

Compounds of general formula (VIII) and VIIb have valuable pharmacological properties.

Particularly preferred compounds of formula (VIIa) include the following substituents

3,7-diazabicyclo [3.3.] nonane:

N-isopropyl-N ^/ - (2-methylpropyl) -9,9-pentamethylene;

N-isopropyl-N'-jciklohexil nietilj ^^ - di-n-butyl;

N-n-butyl-N '- (2-methylpropyl) -9,9-dimethyl-;

N-n-butyl-N '- (cyclohexylmethyl) -9,9-dimethyl-;

N-n-hexyl-N '-methyl-9,9-diethyl;

N- (2-methylpropyl) -N '- (3-butenyl) -9,9-di-n-propyl;

N-n-butyl-N- (3-butenyl) -9,9-dimethyl.

Particularly preferred compounds of formula (VHb) are the 3,7 diazabicyclo [3.3.1] nonanes with the following substituents:

N, N ^, -dicyl-9,9-dimethyl;

N, N'-di-n-propyl-9,9-diethyl-;

N, N'-di-isopropyl-9,9-dimethyl-;

N, N'-di-isopropyl-9,9-di-n-propyl;

N, N'-di-n-butyl-9,9-dimethylergoline;

N, N'-9,9-tetra-n-butyl;

N, N'-di-n-butyl-9-methyl-9-ethyl;

N, N'-di- (cyclopropylmethyl) -9,9-tetramethylene;

N.N'-di-ii-licxyl-9,9-dimcyl;

N, N'-di-yl-hexyl-9-ethyl-9-yl bulil-;

N, N'-di-n-hexyl-9,9-tetramethylene;

N, N ^, -di- (cyclohexylmethyl) -9-methyl-9-ethyl;

N, N'-di (cyclohexylmethyl) -9,9-pentamethylene;

N, N'-di-n-DCCI! -9,9-dimctil-,

N, N'-di-isopropyl-9-methyl-9-n-propyl, ·

N, N'-di-n-butyl-9,9-triinetilén-;

N, N'-di- (2-propenyl) -9,9-dimethyl-;

N, N'-di (3-butenyl) -9,9-pentamethylene;

N, N'-dj- (3-butenyl) -9,9-dimethyl-;

N, Ndi- (3-bis-tenyl) -9-methyl-9-n-propyl.

The present invention further provides a process for the preparation of a pharmaceutical composition comprising one or more compounds of formula (VIIa) or (VIIb) or a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts of the compounds of Formula I include, inorganic or organic acids, water-soluble or water-insoluble salts (e.g., hydrochlorides, hydrobromides, hydroiodides, phosphates, nitrates, sulfates, perchlorates, acclates, extracts, gluconates, propionates, , salicylates, sulfosalicylates, maleinates, laurates, fumarates, succinates, oxalates, tartrates, stearals, tosylates, (p-toluenesulfonates), 2-hydroxy-3-naphthoates, 3-indoxy-2-naphthoate, naphthalene sulfonates, etc.).

According to the process of the present invention, the 3,7-diazabicyclo [3.3.1] nonane derivatives of formula (I) and their pharmaceutically acceptable acid addition salts can be prepared by:

1) for the preparation of a compound of formula II which is a narrower group of compounds of formula 1, wherein R 1, R ₃ and R ₄ are as defined above, a dinitrile of general formula 111 or a mononitrile of formula IV: in the formulas, R ₁ , R ₃ and R ₄ are hydrolyzed with an acid as defined above, preferably sulfuric acid and / or phosphoric acid; and then, if desired

b) for the preparation of compounds of formula (Va), (Vb) cs (Ve), which are a narrower group of compounds of formula (I), wherein R ₁ , R ₂ , R ₃ and R ₄ are as defined above and R ₆ is for compounds of Ri or _R2 bi) (Va) and (Vb), formula (II) compounds of the formula: - wherein R, R ₃ and R ₄ are as defined above - preferably under basic conditions, - an R ₂ X wherein X is a leaving group, preferably a halogen atom, alkyl3

191 096 sulfonyloxy or optionally substituted phenylsilonyloxy and R _{2 is} as defined above; or b ₂ ) in the preparation of symmetrically substituted compounds of formula (Ve), a compound of formula II wherein R ₁ is hydrogen (wherein R ₃ and R ₄ are as defined above), preferably under basic conditions, with a compound of formula R ₆ X reaction: - wherein X and _R6 are as defined above; or b ₃ ) in the preparation of compounds of formula Vb, a compound of formula II wherein R ₁ is hydrogen, wherein R ₃ and R 4 are as defined above, is, in a sequential order, a compound of general formula R ₃ X and R ₂ X reacting a compound of the formula: wherein R ₁ , R ₂ and X are as defined above, preferably under basic conditions;

and or if desired

c) for compounds: Among the compounds of formula (1), (VIIa) and of formula (VHb) - in the formulas R, R _2, R _3, R ₄ and R ₆ are as defined above ej (VIIa), formula in the preparation of compounds, reduction of a compound of formula Vb, wherein R 1, R ₂ , R ₃ and R ₄ are as defined above, preferably with complexed polyhydride; or c ₂ ) in the preparation of symmetrically substituted compounds of formula VHb, a compound of formula Ve wherein R ₃ , R 4 and R ₆ are as defined above, preferably with a complex metal hydride; or c ₃ ) in the preparation of symmetrically substituted compounds of formula VHb, reacting a compound of formula Viaa, wherein R ₃ and R ₄ are as defined above, with a compound of formula ReX, wherein R ₆ and X are as defined above. given - preferably under basic conditions; or c ₄ ) in the preparation of compounds of formula (VIIa), a compound of formula (Via) wherein R ₃ and R ₄ are as defined above, a compound of formula R, X and R ₂ X in the formulas R 1, R ₂ and X are as defined above, optionally under basic conditions; or c _5), (VIIa) for compounds of formula, formula (VIb) or (VIc) compound - preferably under basic conditions - with a compound of formula R ₂ X or a RJX - where R _{(R 2>} R ₃ and R ₄ are as defined above, or c ₆ ) in the preparation of symmetrically substituted compounds of Formula VIIb, a compound of Formula VIb is reacted, preferably under basic conditions, with a compound of Formula RiX or a compound of Formula VIc. reacting a compound of formula ( _II ), preferably under basic conditions, with a compound of formula R ₂ X wherein R 1, R ₂ , R ₃ and R 4 are as defined above; In the preparation of these _7), (VIb), compounds of formula - aliolRj, R ₃ or R ₄ in the above jelentésű- formula (VIa) compound of formula - wherein R ₃ and R ₄ are as defined above - RJX with a compound of formula - wherein R, and X is as defined above, preferably under basic conditions, and if desired, the compound of formula (I) obtained according to any of the above processes is converted into a pharmaceutically acceptable acid addition salt.

The final products of formula (VIIa) are preferably prepared by processes a), bj) or b ₃ ) and ej). The final products of formula (VHb) are preferably prepared according to the procedures a), b ₂ ), e ₂ ). Intermediates of the above processes are particularly preferred.

The 2,4,6,8-tetraoxo-3,7-diazabicyclo [3.3.1] nonane derivatives of the general formula (II) can be prepared analogously to the procedure described in J. Am. Chem. Soc., 1958, 80, 3915. by reaction of a dinitrile of formula (III) or a mononitrile of formula (IV) with a highly concentrated acid-water mixture. The acid used in the process is e.g. sulfuric acid or phosphoric acid may be used.

The dinitriles of formula (III) are known in the literature or may be prepared in an analogous manner to known procedures. Preparation of III Compounds by Condensation of an Alkylidene-Cectic Acid Ester with Cyanoacetamide (Org. Syn. 39, 52); or by reaction of cyanoacetic ester and ketone in ammonia alcohol (Org. Syn. 36, 28).

The mononitriles of formula (IV) are known in part from literature and by condensation of the corresponding ketone and cyanoacetamide in an alkaline medium [J. Chem. Soc. 99, 422 (1911)].

The 2,4,6,8-tetraoxo-3,7-diazabicyclo [3.3.1] nonanes of formula II, their N-monoalkyl derivatives (compounds of formula Va) and the N, N'- reduction of their dialkyl derivatives (Vb and Ve) can be carried out by methods known per se (see, e.g., J. Am. Chem. Soc. 78, 2582, (1956) or Israel J. Chem. 4, 38). (1966)]. Complex metal hydrides such as lithium aluminum hydride or sodium borohydride in the presence of Lewis acids are particularly preferably used as reducing agents.

The reduction is preferably carried out with lithium aluminum hydride in a 70:30 mixture of tetrahydrofuran and toluene. Contrary to the methods quoted above or those described in Eur. J. Med. Chem. 12, 301 (1977), it has been found that the conversion in this solvent mixture is complete within a relatively short ice-up time (usually 2-4 hours). . In cases where the reducing agent is difficult to access due to spatial reasons

4,191,096 (e.g. N-isopropyl), longer reaction times are required. The reducing agent is preferably used in an excess of 200-400%.

When the starting materials R 1 and / or R _{2 represent} unsaturated groups (i.e. alkenyl or alkynyl), sodium bis (2-methoxyethoxy) dihydroaluminate is preferably used as the reducing agent.

Alkylation of tetraoxo compounds of formula (II) or (Va) or compounds of formula (Via), (VIb) or (VIc) obtained by reduction under basic conditions (e.g. with sodium hydride in dimethylformamide, · alkali-phenoxycarbonate in dimethylformamide; with sodium methylate in methanol; with sodium isopropylate in isopropanol, sodium amide in toluene or xylene) using known principle of phase transfer catalysis. Alkylation, especially for the tetraoxo compounds of formula (II), (Va) or (Vb) wherein R 1 is hydrogen, is preferably carried out at higher temperature with sodium hydride or alkali metal carbonate in dinethylformamide.

In the above processes, the starting materials are preferably used in stoichiometric proportions. However, in the alkylation of the compounds of the formulas II and VI, the proton cleavage or alkylating agent is preferably used in an excess of 25-70%.

In alkylating agents R, X, R ₂ X and R ₆ X, X is a leaving group known per se. Suitable alkylating agents are preferably the corresponding alkyl halides, tosylates, brosylates or mesylates, in particular alkyl halides, particularly preferably chlorides or bromides. Alternatively, the alkylating agents may be prepared in situ from the corresponding alcohols, e.g. Mitsunobu (Synthesis 1981, p. 1), which does not require the addition of a separate proton scavenger.

The reactions may be carried out under normal or elevated pressure; we can usually work under normal pressure.

The reactions are generally carried out in an inorganic organic solvent or a mixture thereof with water. Suitable inert organic solvents are preferably ethers (e.g., diethyl ether, dioxane or tetrahydrofuran), halogenated hydrocarbons (e.g., methylene chloride or carbon tetrachloride) or dimethylformanediol or acetone and the like. It can be used.

The reaction temperature is usually ca. 20 ° C and approx. It may be in the range of 200 ° C and preferably 40 to 150 ° C.

Separation of the mono- and dialkylated products, if necessary, can be carried out by conventional methods (e.g., alkaline extraction or chromatographic separation).

The process of the present invention has succeeded in providing a wide variety of substituent types. Thus, in particular, diazabicyclo [3.3.1] nonanes having a symmetric or asymmetric substitution in the 9-position have been obtained by appropriate selection of the R ₃ and R ₄ groups in the starting materials (III) and (IV). On the other hand, by means of the choice of (II), (Va), (VIa), (VIb) or (VIc) and the corresponding compound RJX and _R2 -X alkylating agent of general kcpletű N, NN N'szimmclrikus -aszimmetrikus diazabicikloL3.3- 1] nonanes could be produced.

When R 1 and R ₂ and R ₃ and R _{4 have} different meanings, a mixture of stereoisomers is obtained at different stages of the process. Separation of the stereoisomers may be accomplished by methods known per se (e.g., precipitation of the salt fraction, column chromatography fractionation, or treatment of the aqueous solution at various pHs). When R ₃ and R _{4 are} different groups, the separation is preferably carried out on the diazabicyclo compound of formula (II), (Va) or (Vb) or the diazabicyclo compound of formula (VIb) or (VIc) [3.3.1]. with nonanes.

The acid addition salts may be prepared in a manner known per se by reaction of a basic compound of formula (I) with a pharmaceutically acceptable acid.

Of (VIIa) and (VIIb) compounds - i.e., Z, and Z ₂ liclyén separately are hydrogen and R, and R ₂ liclyén C1-12 alkyl, C2-12 alkenyl, or bonded via a C1-3 alkylene The compounds of formula (I) containing from 3 to 6 carbon atoms of the cycloalkyl group, and their pharmaceutically acceptable acid addition salts, possess valuable pharmacological properties and, in particular, have an oxygen-saving, cardiac and cardiac-regulating effect. The above new compounds show good efficacy and are physiologically well tolerated. The novel compounds of formulas (VIIa) and (VIIb) exhibit satisfactory anliarhythmic activity at low doses. In addition, they have a negligible adverse effect on the ability of the heart to contract. This means that the compounds of formulas (VIIa) and (VIIb) have a very favorable relationship between the antiarrhythmic activity and the negative inotropic side effects which prolong the heart refraction time and exhibit a wide therapeutic range. The compounds of formulas (VIIa) and (VIIb) surprisingly exhibit positive inotropic activity in low doses.

The effect of tcszt compounds on myocardial oxygen utilization in animal studies by NeiU [Neill W. A., Levine Η. H., Wagnian F.J., Gorlin R .: Circulalion Researcli 12, 163 (1963)]. The circulating values required for the experiment - systolic blood pressure and heart rate - according to Buschmann et al., Buschmann, G., Schumacher, W., Buciden, R. and Kiihl, U.G., J. Cardiovasc. Pharmacol. 2, 777-795 (1980)]. Table 1 shows that the compounds of the present invention reduce the product of heart rate and systolic blood pressure and thereby result in oxygen purification of the heart. This effect is due to their experience with intravenous (i.v.) and intraduodenal (i.d.) administration of the test compound and is due to the efficacy of the test compounds.

The antiarrhythmic activity of the novel compounds obtainable by the process of the present invention has been demonstrated in intact experimental animals with experimentally induced rhythm disorders. In rats, aconitine was administered by continuous intravenous infusion of

191,096

Effect of test compound on heart rate (FRQ), systolic blood pressure (PJ, and double product (DP)) in anesthetized rat

Table 1

Test compound of formula (I) Dose [ΜιηόΙ / kg] FRQ Ll / min] P _s [Hmmmm] DP [MmHg / minXlOOO] Change in DP (%) pre Values 0 372 104 39 - Example 3 No. 302 ^x) 13.5 i.v. 174 147 25 -36 pre Values 0 406 101 41 - Example 3 No. 302 ^x) 100 i.d. 238 125 30 -27

^χ ) = ditartrate.

grams show significant disturbances in the heartbeat rhythm (eg ventricular extravasation). Effect of test chemical on male Wistar rats infused with aconitine, 280 g to 350 g, by the method of Raschak [Raschak, M., Arzneim. Forschung (Drug Res.), 25, (4) 639-641 (1975)] and the results are summarized in Table 2. The time taken for the test compound to be administered at a dose of 6.0 μιηόΙ / kg iv (one-half of the ip LD ₅₀ values in the mouse; LD ₅₀ po 1038 μηιenként / kg) per unit time of continuous aconitine infusion (ES) was determined. ). This value is compared with the corresponding value in the control experiment (isotonic saline instead of drug).

Table 2 shows the effect of equidox dose of Lidocain (a well-established and recognized antiarrhythmic agent used in human medicine) for comparison purposes.

Table 2

Antiarrhythmic activity in the aconitine test in rat

Test compound Time to ES [minutes] Change [%] Carrier 0 6.7 - Example 3: Ditartrate No. 302 6.0 8.2 + 23 Carrier 0 6.3 - lidocaine 10.0 6.6 + 5

The antiarrhythmic activity of the new compounds of the present invention is further experimentally determined in 300-400 g female guinea pigs (Albino Pirbrigt) by determining the functional refraction time of the left atria, by electrical twin stimulation, by Govier W. J. Pharmacol. Exp. Ther. 148 (1), 100-105 (1965)]. All antiarrhythmics currently known and used in medicine prolong functional refraction time. This method also allows the effects of the active ingredient on myocardial contractility to be investigated. In Table 3, FRP 125% 6 is the concentration (in μιηόΙ / l) that results in an extension of the functional refractive time to 125% 18 minutes after test compound administration. Similarly, F75% is the concentration at which the contractile force is reduced to 75% of baseline. The F 75% / FRP 125% ratio is the ratio of the dose reducing the contraction force and prolonging the refraction time. The latter quotient suggests the therapeutic breadth of the antiarrhythmic effect on isolated organs (Greef, K., 1969, 35, 88-97).

The direct effect of the test compound on heart rate (FRQ) is determined in a spontaneous, isolated right atrial fossa. Female guinea-pigs (Albino Pirbright) weighing between 300 and 400 g are used as experimental animals. In Table 3, FRQ 75% is the concentration (in μηιόΙ / l) that causes the frequency to decrease to 75% from baseline 20 minutes after test compound administration.

Table 3 shows that the novel compounds of the present invention do not exhibit any undesirable negative inotropic effects, but also exhibit antiarrhythmic and cardiac rate lowering effects at very low concentrations.

Table 3

Effect on Spontaneous Frequency of Right Guinea Pig Guinea Frequency (FRQ) and on contractile force (F) and Functional Refraction Period (FRP) of electrically stimulated left guinea pig guinea pig '

A compound of formula (I) Effective concentration μηιόΐ / ί FRP 125% F 75% / / FRP 125% hánya- dos 75% F 75% Example 3, in the form of ditartrate # 302 3 104 1 104 comparator in the form of ditartrate approx. 125 approx. 125 122 approx. 2

-611

191,096

Table 3 also compares the results obtained with the known N, N ⁽ -9,9-tetramethyl-diazabicyclo [3.3] nonane), which is the structurally closest known known compound to the new compounds of the present invention. that the novel compounds of formula (I) are very far superior to the therapeutic efficacy of the known compound, however, it is noteworthy that the known diazabicyclo [3.3. 1] the nouan derivative surpasses the therapeutic efficacy of well-known drugs known in practice, such as Lidocaine.

An advantage of the novel compounds of the present invention is the combination of an oxygen-sparing rhythm regulator, a heart rate modifier and a positive inotropic effect.

Based on the above profile, the compounds of formula (I) may be used in ischemic heart disease, life-threatening arrhythmias and cardiac arrest.

The daily dose of active ingredient is generally 0.1 to 10 mg / kg. Administration may be by the enthral or parenteral route.

It is a further object of the present invention to provide a pharmaceutical composition comprising admixing one or more compounds of formula (VIIa) or (VHb) or a pharmaceutically acceptable acid addition salt thereof with inhaled pharmaceutical carriers. These compositions are prepared by methods well known in the art of pharmaceutical manufacture. The pharmaceutical compositions are e.g. in the form of tablets, dragees, capsules, powder mixes, granules, aqueous or oily suspensions, emulsions, syrups (for oral administration), suppositories (for rectal administration) or sterile injectable suspensions or solutions (for parenteral administration).

The following examples further illustrate the process without limiting the invention to the examples.

Example 1

General description of the cyclization process leading to the tetraoxo-3,7-diazabicyclo [3.3.1] nonane derivatives of formula (II) g (dinitrile (III) prepared analogously to Method 39, 52 of Org. Synth.) g of inonyl nitrile of formula IV [J. Chem. Soc., 99, 10, 422 (1911)].

100 ml of acid are heated to 120 DEG C. to 140 DEG C. with stirring until completely dissolved. Contain the contents of the flask at ca. After 10-15 minutes, pour into ice water. The excellent tetraoxo compound of formula II is filtered off under vacuum, optionally recrystallized (preferably from ethanol) and dried. Characteristic data for the compounds prepared by the above method are shown in Table 4a. and 4b. It is summarized in a table.

Example 2

General description of alkylation of tetraoxo compounds of formula II

2a. EXAMPLE 1: General description of the dialkylation of a tetraoxo compound of formula II (R 1 -H) with a compound of formula R ₃ X _{6 to a} compound of formula Ve

0.1 Moles of the tetraoxo compound (II) (35) prepared in Example 1 are weighed into a preheated three-necked flask, mixed with 200 ml of anhydrous dimethylformamide and heated to 60-70 ° C. 0.25 M sodium hydride (100% w / w) was added portionwise and the mixture was refluxed for 1 hour. The reaction mixture was cooled and a solution of 0.3 mol of alkylating agent in 50 ml of anhydrous dimethylformamide was added rapidly. Preparation of Tetraoxo Compounds of Formula II (Ri = H)

Song R ³ R ⁴ Acid (t% by volume) Mp (° C) mining, % 101. ^x) -CHj -Cll ₃ 60% 1I ₂ SO ₄ Over 350 50 102nd -C ₂ H _s -c ₂ h ₅ 60% H ₂ SO ₄ 230 ' 61 103rd nC ₃ H ₇ nC ₃ H ₇ - 60% II ₂ S0 ₄ 190 70 104th nC ₄ H ₉ nC ₄ H ₉ - 85% H ₂ SO ₄ 195-199 45 105th _ (CII ₂ ) ₃ - 60% I1 ₂ SO " Over 350 70 106 ^x) - (CH ₂ ) ₄ - 60% H ₂ SO ₄ 310 81 107 ^x) - (CH ₂ ) _s - 60% H ₂ SO ₄ 40 81 108. ^x > -ch ₃ -c ₂ h ₅ H ₂ SO ₄ / H ₃ PO ₄ 1: 1 324-326 84 109. ^x) -ch ₃ nC ₃ H ₇ - H ₂ SO ₄ / H ₃ PO „1: 1 275 65 110th —C ₂ h ₅ nC ₄ H ₉ - 70% H ₂ SO ₄ 140 65

^χ ) = not a compound of the invention.

-713

191,096

4b. Preparation of Tetraoxo Compounds of Formula II (Rp £ H)

Song R ¹ R ³ R ⁴ Acid (volume%) Mp (° C) Yield * ^ % 150th n-C4H9- -Cl _{1 3} Cll ₃ i I ₂ SO ₄ / H ₃ PO ₄ 1: 1 175-178 56 151st -CH ₂ -CH (CH ₃ ) ₂ nC ₃ H ₇ - nC ₃ H ₇ - H ₂ SO ₄ / H ₃ PO ₄ 1: 1 149-153 85 152nd I1-C4H9- nC ₄ H ₉ - 60% H ₂ SO ₄ 140 86 153rd n CeHn- -c ₂ h ₅ -C ₂ H _s H ₂ SO ₄ / H ₃ PO ₄ 1: 1 oil 91 154th -CH ₂ -CH (CH ₃ ) ₂ (CH ₂ ) _s - H ₂ SO ₄ / H ₃ PO ₄ 1: 1 ^ 82 80

Yield ^.

and the reaction mixture was heated under reflux for an additional 3 hours. Most of the solvent was removed in vacuo. The residue is taken up in methylene chloride and washed with 20% sodium hydroxide solution. The aqueous phase was re-extracted with methylene chloride. The combined organic layers were washed several times with water, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from ether-hexane.

Alkylation can also be accomplished by using alkali metal carbonate as the 39 base instead of sodium hydride. In this case, the general procedure is as follows:

0.1 Moles of the tetraoxo compound (II) prepared in Example 1 are weighed into a preheated three-necked flask, mixed with 0.25 g of alkali metal carbonate and 200 ml of anhydrous dimethylformamide and heated at 120 ° C for 1 hour. on. The reaction solution was cooled and a solution of 0.3 mol of alkylating agent in 50 ml of anhydrous dimethylformamide was added dropwise. The reaction mixture is refluxed until the conversion is complete and the residue obtained after conventional work-up is crystallized from hexane-hexane.

5a. The following table shows representative data for the compounds prepared by the above procedure. In the "base" column, "A" refers to sodium hydride, while "C" refers to alkali carbonate.

2b. example

The tetraoxo compound of formula (IJ) (R, ΨΙΙ)

General description of monoalkylation of R ₂ with compound of formula X to give compound of formula Vb

2a. The procedure described in Example 1b is carried out with the exception that half of the amount of sodium hydride or alkali metal carbonate and alkylating agent is used.

2b. In a manner analogous to that described in Example 5c, alkylation of the compounds of formula (VIa) may be carried out in accordance with Example 5c. The compounds of formula VIb listed in the Table are prepared.

5a. Table (II) tetraoxo compounds of the formula (R = II) dialkilezcse carried out with alkylating agents of formula R ₆ Xáltalános, resulting in compound of formula (Ve) (Ve) ⁺ Compounds of formula X, R ₆ X in

Evade-

Song R ⁶ R ⁶ R ³ R ⁴ x ⁺ Base Mp (° C) pro- duction *) % Two hundred and first -C ₂ H ₅ -c ₂ h ₅ -CH ₃ -ch ₃ Br THE 152-153 60 202nd I1-C4H9 - nC ₄ H ₉ - -ch ₃ -ch ₃ Br C 97 61 203rd nC ₆ H ₁₃ - nC ₆ H ₁₃ - -ch ₃ -ch ₃ Br THE 68-69 63 204th ch ₂ -ch 1 ch ₂ = ch -ch ₃ -ch ₃ Br C 91 76 1 -ch ₂ -ch ₂ 1 -CH ₂ -CH ₃ 205th iC ₃ lI ₇ - iC ₃ H ₇ - CH dl, Br Λ 99-101 37 206th i-Ci ₀ H ₂₁ - i-CioH ₂ i— -ch ₃ -ch ₃ Br THE 63 56 207th nC ₃ H ₇ - nC ₃ H ₇ - -c ₂ h ₅ —C ₂ h _s cl THE 94 '59 208th ic ₃ H ₇ - iC ₃ H ₇ - n-C 3 H ₇ - I1-C3H7- Br THE 145-147 30

-815

191,096

5a. Continue Table

Song R ⁶ R ⁶ R · ¹ R ⁴ X ⁺ Base Mp (° C) Evade- pro- duction * ^ % 209th CH, -CH ₃ nC ₄ H ₉ - 'nC ₄ H ₉ - J THE 135-137 46 210th 11-C4H9 - 11 C4H9- nC ₄ 1Ί 9— i-C ₄ H ₉ - bt THE 73-75 85 211th nC ₆ H 13— nC <iH ₁₃ - - (CH ₂ ) "- Br THE 70 30 212th -CH ₂ - <J -ch ₂ - <3 - (CH ₂ ) ₄ - cl THE 160-161 58 213th - ^ch '-O 0-CH - (CH ₂ ) _; - Br THE 140 43 214th ch ₂ = ch 1 -ch ₂ ch ₂ ch ₂ = ch 1 -ch ₂ -ch ₂ - (CH ₂ ) _} - Br C 120 54 215th n C4II9- nC ₄ H ₉ - -ch ₃ -c ₂ h ₅ Br THE 82 81 216th -ch.-Q -CH-θ CH, -c ₂ h ₅ Br THE 112-115 45 217th -C ₃ H ₇ - ic ₃ ti ₇ - CH, hC ₃ H ₇ - Br THE 103 47 218th ch ₂ = ch 1 -ch ₂ -ch ₂ ch ₂ = ch 1 -ch ₂ -ch ₂ CH, nC ₃ H ₇ - Br THE 57 45 219th nC ₆ Hi ₃ - nC ₁₃ H _ö - -C ₂ H _s hC ₄ H ₉ - Br THE oil 38 220th ch ₂ = ch 1 '-ch ₂ -ch ₂ ch ₂ = ch 1 -ch ₂ -ch ₂ CH, CH, Br THE 128-130 59 221st nC ₄ H ₉ - nC ₄ H ₉ - - (CH ₂ ) ₃ - Br THE 110 49

^χ ) Extraction.

5b. Table II: Monoalkylation of Tetraoxo Compounds of Formula II with Compounds of Formula (R 1 H) R ₂ X to Compounds of Formula Vb in Compound Vb ⁺ = X, R ₂ X

Song R ¹ R ² R ³ = R ⁴ X ⁺ Base Mp (° C) Evade- pro- duction * ^ % 250th nC ₄ H ₉ - -CH ₂ -CH (CH ₃ ) ₂ -ch ₃ Br THE 80. : 81 251st nC ₄ H ₉ - ch ₂ = ch 1 -ch ₂ -ch ₂ -ch ₃ Br THE 80-83 66 252nd nC ₄ H ₉ - - ™, -0 -ch ₃ Br THE 100 64 253rd -ch ₃ ii-C ₆ Hi ₃ - -C ₂ H _s J THE 93-96 31 254th ic ₃ h ₇ - 0-CH nC ₄ H ₉ - Br THE 85 48 255th -CH ₂ CH (CH ₃ ) ₂ ch ₂ = ch 1 -ch ₂ = ch ₂ nC ₃ ll ₇ - Br THE i oil 38 256th -C ₃ H ₇ - -CH ₂ -CH (CH ₃ ) ₂ - (CH ₂ ) ₄ - Br THE 101 30

-917

191,096

c. Table (Compounds of Formula VTbj)

Song R ¹ R ³ R ⁴ Fp;. C (0.01 mmHg) Evade- pro- duction (%) 280th • nC ₄ H ₉ - -ch ₃ - -ch ₃ - 145 40 281st Cll ₂ / 220 35 282nd 2-methyl- butyl '(CH ₂ ) ₅ 180 51 283rd iC ₃ H ₇ - -ch ₃ CH, 150 40 284th n-Chili - -ch ₃ -Cl _{1 3} 150 48 285th c ₂ h ₅ - -ch ₃ -CH ₃ 131 36

Example 3 General description of the reduction of dialkylated tetraoxo compounds of formula (Vb) or (Ve) to the 3,7-diazabicyclo [3.3.1] nonane derivative of formula (VIIa) or (VIIb)

In a preheated three-necked flask, add a solution of 0.1 moles of lithium aluminum hydride in a mixture of 70 ml of anhydrous tetra10 hydrofuran and 30 ml of anhydrous toluene. A solution of tetraoxo (Vb) or (Ve) (0.025 mol) in tetrahydrofuran-toluene (70 ml, 70:30) was slowly added dropwise to the solution at 80 ° C. The reaction mixture is heated at 120 'C for 2-4 hours and then subjected to basic hydrolysis. The mixture was extracted with methylene chloride, and the organic phase was dried over anhydrous magnesium sulfate and evaporated. Purify the residue by vacuum distillation. Table 3 3-diazabicyclo [3.3. Reduction of l} -nonan derivatives to compounds of formula (VHa)

Song R ¹ R ² R ³ R ⁴ Boiling point (° C, 0.1 Torr) mining, % Three hundred and first -C ₂ H _s -c ₂ h ₅ -CH ₃ -ch ₃ 160-170 64 302nd nC ₄ H ₉ - Í1-C4H9 - -ch ₃ -ch ₃ 130 48.5 303rd nC ₆ H ₁₃ - nC ₆ Hi3— -ch ₃ -ch ₃ 210-220 84 304th iC ₃ H ₇ iC ₃ H ₇ -ch ₃ -ch ₃ 100-120 37 305th nC _{) 0} H ₂₁ - nC | ₀ H ₂ i— -ch ₃ -ch ₃ 230 60 306th n-CiH ₇ - nC ₃ H ₇ - -c ₂ h ₅ -c ₂ h ₅ 140-150 65 307th -C ₃ H ₇ - iC ₃ H ₇ - 11 C ₃ H ₇ - nC ₃ H ₇ - 150-160 58 308th n CöHíj- nC ₆ H ₁₃ - - (CH ₂ ) ₄ - 250 77 309th -ch ₂ ~ o -ch ₂ - <j _ (CH ₂ ) ₄ - 230 79 310th 11 -C4H9 - I1-C4H9 - -ch ₃ -C ₂ 11 ₅ 180-200 83 311th n CeHjj- nC ₆ Hi3- -c ₂ h ₅ nC ₄ H ₉ 230 40 312th n CöHia- -ch ₃ -c ₂ h ₅ -c ₂ h _s 130 31 313th -CH ₂ - -ch ₂ - _ (CH ₂ ) _s - 102 ^x) 75 314th -ch ₂ - -ch ₂ - -CII3 -c ₂ h ₅ 36x ⁾ 75 ' 315th -C ₃ H ₇ - -C, H ₇ - -CHj nC ₃ H ₇ - 150 51 316th -C ₃ H ₇ - -CH ₂ -CH (CH ₃ ) ₂ - (CH ₂ ) _s - 150 66 317th í-c ₃ h ₇ - -ch ₂ - nC ₄ H ₉ - nC ₄ H ₉ - 190-200 33 318th I1-C4H9- -ch ₂ - -CHj -ch ₃ 160 78 319th I1-C4H9- -CH ₂ -CH (CH ₃ ) ₂ -ch ₃ -ch ₃ 160-170 74 320th I1-C4H9 - nC ₄ H ₉ - - (ch ₂ ) ₃ - 170 83 321st I1-C4H9 - nC ₄ H ₉ - rt-C ₄ H ₉ - nC ₄ H ₉ - 210 76

^χ ) = melting point.

-1019

191,096. Typical data for the obtained 3,7-diazabicyclo [3.3.1] nonane derivatives are shown in Figure 6a. This is shown in the table.

The nitrogen atom of the alkenyl group is a substituted N, N-disubstituted tetraoxo compound of formula (Vb) or (Ve) with sodium bis (2-methoxyethoxy) -dihydroalinnate (trade name Red-A1 ^R ) in an analogous manner to the above procedure. reduced in toluene. Typical data for the compounds obtained are shown in Figure 6b. Includes table.

Example 4: General description of the conversion of compounds of formula (Via) into compounds of formula (VIIa) and (VIIb)

A solution of the compound (Via) in tetrahydrofuran is cooled to -10 ° C. An equimolar amount of n-butyllithium solution (as a 15% solution in hexane) was added dropwise to the solution while stirring. After one hour, an equivalent amount of alkylating agent R RX is also added at -10 ° C. The reaction mixture is slowly allowed to warm to room temperature and after 6 hours is cooled again to -10 ° C and reacted sequentially with n-butyllithium and an alkylating agent R ₂ X as described above. The reaction mixture was mixed with water the next morning, extracted with ether, dried over anhydrous magnesium sulfate, and the organic phase was evaporated. The compounds of formula (VIIa) and (VIIb) are obtained by vacuum distillation.

By the above procedure, e.g. the following compounds are prepared:

(a) in Article 319; by alkylation with n-butyl bromide and isobutyl bromide, yield

30%

(b) Section 321; by 45% two-step alkylation with n-butyl bromide.

EXAMPLE 5 General Description of the Conversion of Compounds of Formula (VIIb) and (VI <j) to Compounds of Formula (VIIa) and (VIIb)

The bispidine compound (VIb) and (VIc) are dissolved in tetrahydrofuran and the solution is cooled to -10 ° C. The resulting solution was stirred while stirring

An equimolar amount of a solution of n-butyllithium (15% in hexane) was added dropwise at this temperature. After one hour, an equivalent of Rt X and R ₂ X _was also added at -10 ° C. it was allowed to warm slowly to room temperature and stirred for 6 hours to complete the reaction.

Water was added to the reaction mixture, extracted with ether, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to vacuum distillation.

By the above procedure, e.g. the following compounds are prepared:

(a) in Article 318; compound by alkylation with cyclohexylmethyl bromide in 65% yield;

6b. Reduction of N-alkenyltetraoxo Compounds of Formulas (Vb) and (Ve) to 3,7-Diazabicyclo [3.3.1] Nonate Derivatives of Formula (Vlla) Compounds of Formula Vlla

Song R ¹ R ² R ³ R ⁴ Boiling point (° C, 0.1 Torr) Yield * % 350th -CH ₂ -CH = CH ₂ -CH ₂ -CH = CH ₂ -ch ₃ -ch ₃ 160 24 351st ch ₂ = CH 1 -ch ₂ -ch ₂ ch ₂ = ch 1 -ch ₂ -ch ₂ - (CH ₂ ) _s - 175 46 352nd ch ₂ = ch 1 -ch ₂ -ch ₂ Cl l ₂ = CH 1 -ch ₂ -ch ₂ -ch ₃ -ch ₃ 150 41 353rd -CH ₂ -CH (CH ₃ ) ₂ -CH ₂ -CHj 1 ch ₂ = ch nC ₃ H7- nC ₃ H ₇ - 170 82 354th η - (? 4Η ₉ - -ch ₂ -ch ₂ 1 ch ₂ = ch -CK ₃ -ch ₃ 165 49 355th ch ₂ = ch 1 -ch ₂ -ch ₂ ch ₂ = ch 1 -CH ₂ -CH ₂ -ch ₃ nC ₃ H ₇ - 130 45

* = Yield.

-1 121

191,096

(b) Section 302; Compound by alkylation with n-butyl bromide in 55% yield.

Example 8

Preparation of tablets

Example 6 Monoalkylation of a tetraoxo compound of formula II (R _x is hydrogen) with a compound of formula R ₂ X to give a compound of formula Va: g. Compound (Table 4a) is suspended in 500 ml of dimethylformamide and then 30 g of powdered sodium carbonate are added. The mixture was heated to 140 ° C for 2.5 hours with vigorous stirring, then ca. It is cooled to 30-40 ° C and the insoluble material is filtered off (residual sodium carbonate and about 25% starting material). The filtrate was cooled to 20 ° C and 20.6 g of n-butyl bromide was added dropwise with stirring. The reaction mixture was stirred at room temperature for 20 hours and then evaporated to dryness in an oil vacuum high vacuum. To the residue was added ethyl acetate (300 mL) and water (basic sodium hydroxide, 300 mL) to pH 10, and the mixture was stirred until completely dissolved.

The two phases are separated; a portion of the desired compound immediately enters the aqueous phase. The ethyl acetate phase consists of a mixture of mono- and double-substituted products.

The aqueous phase was extracted with methylene chloride (3 x 300 mL) (TLC: 1: 1 ethyl acetate / cyclohexane).

The combined methylene chloride extracts were dried over sodium sulfate and evaporated. 5 g of mono-substituted 150 g. yielding compound (Table 4b).

The yield can be increased by extracting the ethyl acetate phase with water alkalinized to pH 10. An additional ca. 2 g. Compound (Table 4b) and from the ethyl acetate phase ca. 3 g of dibutyl compound (Compound 202, Table 5a) are isolated.

Example 7

General description of salt formation (preparation of salicylate salts)

The bispidine base and salicylic acid are dissolved separately in ether; the base and the acid are used in equivalent amounts. An ethereal solution of the acid is added dropwise to a solution of the bispid base under ice-cooling and stirring. The resulting solid was filtered and dried.

By the above procedure, e.g. the following compounds are prepared:

(a) Section 351; salicylic acid salt of the compound, m.p. 116-119 ° C;

(b) Section 353; m.p. 139-143 ° C.

8-10. Examples 1 to 5 illustrate the preparation of pharmaceutical compositions containing the compounds of the present invention.

We make tablets of the following composition: component Active ingredient (eg Example 3, Table 6a) Quantity, parts No. 302 ditartrate of its compound) 20 corn starch 30 Koilidon 25 ^R 5 Lactose 55 Magnesium stearate 2 Hydrogenated castor oil 1 Total weight: 113

The active ingredient is mixed with corn starch and finely powdered lactose in a suitable mixer. The resulting mixture was moistened with a 20% isopropanol solution of polyvinylpyrrolidone (Koilidon 25, manufactured by BASF). If necessary, additional isopropanol is added. The wet granulate was passed through a 2 mm sieve, dried in a tray at 40 ° C and passed through a 1 mm sieve (Frewitt apparatus). The granulate is mixed with magnesium stearate and hydrogenated castor oil and compressed into 113 mg tablets containing 20 mg of the active ingredient.

Example 9

Preparation of Capsules Capsules having the following composition are prepared:

Component Quantity by weight

Active ingredient (eg Example 3, Table 6a)

302, Ditartarate) 20

Maize starch 20

Lactose 45

Koilidon 25 ^R 3

Magnesium stearate 1.5

Aerosil 200 ^R 0.5 total weight: 90.0

The active ingredient is mixed with corn starch and finely powdered lactose in a suitable mixer. The resulting mixture is moistened with a 20% isopropanol solution of polyvinylpyrrolidone (Coilidone 25) and additional isopropanol is added if necessary. The wet granulate is passed through a 1.6 mm sieve (Frewitt), dried in a tray at 40 ° C and passed through a 1 mm sieve (Frewitt). The granulate was mixed with magnesium stearate and silica gel aerosil (Aerosil 200, Degussa) to fill the resulting mixture into size 4 hard gelatine capsules in an automatic capsule filling machine to form 90 mg capsules containing 20 mg of active ingredient.

-1 223

191,096

Example 10

Preparation of ampoules

We make ampoules with the following composition:

Component Quantity (per vial)

Active ingredient (Example 3, Table 6a)

302, ditartrate) 5 mg

Sodium chloride 16 mg

Water for injections gives 2.0 ml

Sodium chloride is dissolved in water for injection and the active ingredient is added and dissolved with stirring. The solution is made up to volume with water for injection. The mixture was filtered through a membrane filter (0.25 μ) and filled into 0.15 ml brown glass ampoules. The vials were sealed by melting and steam sterilized at 121 ° C for 30 minutes. Each ml of solution for injection contains 5 mg of the active substance.

PATENT CLAIMS

Claims (14)

1.) For the preparation of compounds of the formula: Among the compounds of formula (I) (II) (wherein R |, R ₃ and R ₄ are as defined above), (III) a dinitrile or the formula (IV) mononitrile (wherein R 1, R ₃ and R ₄ are as defined above) is hydrolyzed with an acid, preferably sulfuric acid and / or phosphoric acid; and then in the desired act A process for the preparation of diazabicyclo [3.3.1] nonane derivatives of the formula I and their pharmaceutically acceptable acid addition salts, comprising: Z ₁ and Z ₂ together form an oxo group or independently represent a hydrogen atom; R 1 and R ₂ are each independently hydrogen, C 1 -C 12 alkyl, C 2 -C 6 alkenyl, or C 3 -C 6 alkylcycloalkyl bonded via C 1 -C 3 alkylene; R ₃ and R ₄ each independently represent C 1-6 alkyl or together form C 3-6 alkylene; with the condition that A) when R ₍ and R ₂ are hydrogen) i) Z and Z _{2 are taken} together to form an oxo group other than R ₃ and / or R ₄ or a tetra or pentamethylene group; or ii) Zn and Z ₂ are each hydrogen, at least one of R ₃ and R ₄ is other than methyl; obsession B) if only one of R 1 and R ₂ represents a hydrogen atom, then at least one of R ₃ and R _{4 has} a different meaning than a methyl or ethyl group when the other of R ₁ and R ₂ represents a methyl or ethyl group ; or C) if Ri and _R2 are both other than hydrogen, it azRj-R ₄ groups together contain at least 5 carbon atoms - characterized in that The process according to claim 1, R 1 and / or R @ ₂ is C1-7 alkyl, C2-6 alkenyl or C1-3 bonded via alkylene, preparation of (1) compounds of the formula having a total of up to 7 carbon atoms 35 cycloalkylalkyl group (álról Zj, _Z2 (R ₃ and R ₄ are as defined in claim 1), characterized in that the corresponding substituted starting material is used. 40 For compounds 2) forming a narrower group of the compounds of formula (I), (Va), (Vb) and formula (Ve) (in the formulas, R, R _2, R ₃ and R ₄ are as defined above and R _c is R or R ₂ ). 2j) In the preparation of compounds of the formulas Va and Vb, a compound of the formula II (wherein R 1, R ₃ and R ₄ are as defined above), preferably under basic conditions, with a compound of the formula R ₂ X reacting (wherein X is a leaving group, preferably a halogen, alkylsulfonyloxy or optionally substituted phenylsulfonyloxy group and R _{2 is} as defined above); obsession For the preparation of 2 ₂₎ (Ve) symmetrically substituted compounds, a compound of formula wherein R₁ is a hydrogen atom (II) (wherein R ₃ and R ₄ are as defined above) - preferably under basic conditions - with a compound of general formula R ₆ X (wherein X and _R6 are as defined above), or 2 ₃ ) In the preparation of compounds of formula Vb, a compound of formula II (wherein R ₃ and R ₄ are as defined above) wherein R 1 is hydrogen, is sequentially substituted with a compound of formula R 1X and R ₂ X We reacted (the formulas R, _R2 and X are as defined above), preferably under basic conditions; and / or if desired A process according to claim 1 or 2 for the preparation of compounds of formula (I) wherein R ₁ and / or R _{2 are} straight-chained C 1 -C 12 alkyl or C 2 -C 6 alkenyl (wherein Z ₁ , Z ₂ , R ₃ and R ₂₎ . ₄ is as defined in claims 1 to 45, characterized in that the appropriately substituted starting material is used. 3) In the preparation of compounds of formula (VIIa), a compound of formula (Vb) (wherein R 1, R ₂ , R ₃ and R ₄ are as defined above) is reduced, preferably with a complex metal hydride; obsession ₂ ) in the preparation of symmetrically substituted compounds of general formula (VHb), reduction of a compound of formula (Ve) (wherein R ₃ , R ₄ and R ₆ are as defined above), preferably with a complex metal hydride; obsession 3 ₃₎ symmetrically substituted (VIIb) for compounds of formula, formula (VIa) compound of formula (wherein R ₃ and R ₄ are as defined above), a R, with a compound of formula ₆ X (wherein _R6 and X are as above), preferably under basic conditions; obsession For the preparation of 3 _4), (VIIa) wherein kcpletű compounds of formula (VIa) compound of formula (wherein R ₃ and R ₄ are as defined above) in a RJX and R ₂ a compound of formula X (in the formulas, R, R _2, and X -1 325 191,096 (as defined above) is reacted in any order, preferably under basic conditions; obsession For the preparation of three _5), (VIIa) compounds of formula, formula (VIb) or (VIc) is 5 _r compound of formula - preferably under basic conditions, - an R ₂ X or R, X is a compound of formula is reacted (in the formulas, R, _R2 , R ₃ and R ₄ are as defined above); or 10 3 ₆ ) symmetrically substituted compounds of formula (VIIb) are prepared in the form of flesh by reacting a compound of formula (VIIb), preferably under basic conditions, with a compound of formula (RjX) or a compound of formula (VIIc) - preferably under basic conditions a compound of formula R ₂ X are reacted (in the formulas, R, R _2, R ₃ and R ₄ reports of _2Q is as defined above); obsession For the preparation of 3 _7), (VIb), compounds of the formula (wherein R, R ₃ and R ₄ are as defined above), formula (VIa) compound of formula (wherein R ₃ and R ₄ are as hereinbefore defined), R, X propen compound reacted (wherein R 1 and X are as defined above), preferably under basic conditions, and if desired, the compound of formula (I) obtained according to any of the above processes is converted into a pharmaceutically acceptable acid addition salt. 3) in the preparation of compounds of formula (VIIa) and (VHb), which are a narrower group of compounds of formula (I), wherein R 1, R ₂ , R ₃ , R ₄ and R ₆ are as defined above, A process according to claim 1 or 2 for the preparation of compounds of formula (I) wherein R 1 and / or R ₂ have a branched C 1 -C 12 alkyl or C 2 -C 6 alkenyl group (wherein Z ₁ , Z ₂ , R ₃ and R ₄ are as defined in claim 1, wherein the appropriately substituted starting material is used. A process according to claim 1 or 2 for the preparation of compounds of formula (I) wherein R ₁ and / or R _{2 are} attached to the nitrogen atom via a C 1-3 alkylene group, preferably a methylene group, wherein Z 1, Z _2, R ₃ and R ₄ represents θθ as defined in claim 1), characterized in that correspondingly substituted starting materials are used. 6. The method of any one of claims 1 to 5 For preparing compounds of formula (I), R ₂ represents the same group and R (wherein Z _l Z _2, R ₃ and R ₄ are as defined in claim 1), characterized in that correspondingly substituted starting materials are used. 7. A process according to any one of claims 1 to 6 for the preparation of compounds of formula (I) wherein R ₃ and R _{4 are} alkyl groups having up to 4 carbon atoms (wherein Z 1, Z ₂ , R 1 and R ₂ are as defined in any one of claims 1 to 6). using appropriately substituted starting materials. A process according to claim 7 for the preparation of compounds of formula (I) wherein R ₃ and / or R ₄ is a straight chain alkyl group (wherein Z 1, 7.2, R 1 and R ₂ are as defined in any one of claims 1 to 6). to use the appropriately substituted starting material. A process according to claim 7 or 8 for the preparation of compounds of formula I wherein R ₃ and R _{4 are the} same group (wherein Z ₁ , Z ₂ , R 1 and R ₂ are as defined in any one of claims 1 to 6). characterized in that the appropriately substituted starting material is used. 10. A process according to any one of claims 1 to _{3 for the} preparation of compounds of formula (I) wherein R ₃ and R ₄ together represent an alkylene chain of the formula - (CH ₂ ) _n - (wherein π is 3-5) - (wherein Z ₁ , Z ₂ , R 1 and R ₂ (as defined in any one of claims 1-6), wherein the appropriately substituted starting material is used. 11. A method according to any preceding claim for preparing compounds of formula = O (I) Zi and Z ₂ is combined (where R, R _2i, R ₃ and R ₄ are defined as 1-10. claimed in any one of) characterized in that correspondingly substituted starting compounds are . 12. A method according to any one of claims (1) compounds of formula Z _and Z ₂ represents separately hydrogen (wherein R, R _2, R ₃ and R ₄ are defined as 1-10. claimed in any one of) characterized in that the appropriately substituted starting material. 13. A process according to any one of claims 1 to _3, wherein Z ₂ and Z ₂ are independently hydrogen and R 3 and R _{2 are} C 3-6 cycloalkyl attached via C 1 -C 12 alkyl, C 2 -C 6 alkenyl or C 1 -C 3 alkylene groups. wherein R ₃ and R ₄ are as defined in claim 1, wherein the appropriately substituted starting material is used. A process for the preparation of a pharmaceutical composition having an antiarrhythmic effect, characterized in that at least one compound produced by the process of claim 1 (wherein Z ₁ , Z ₂ , R 1, R ₂ , R ₃ and R ₄ are as defined in claim 13) or a suitable acid addition salt thereof as an active ingredient in admixture with inert solid or liquid pharmaceutical carriers.